Study to Evaluate the Efficacy and Safety of Pemigatinib in Participants With Previously Treated Glioblastoma or Other Primary Central Nervous System Tumors Harboring Activating FGFR1-3 Alterations

Phase 2TerminatedNCT05267106

Incyte Corporation83 enrolled

Overview

This is an open-label, monotherapy study of pemigatinib in participants with recurrent glioblastoma (GBM) or other recurrent gliomas, circumscribed astrocytic gliomas, and glioneuronal and neuronal tumors with an activating FGFR1-3 mutation or fusion/rearrangement. This study consists of 2 cohorts, Cohorts A, and B, and will enroll approximately 82 participants into each cohort. Participants will receive pemigatinib 13.5 mg QD on a 2-week on-therapy and 1-week off-therapy schedule as long as they are receiving benefit and have not met any criteria for study withdrawal.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Glioblastoma Adult-type Diffuse Gliomas

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 99 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Histological, cytological, or molecular confirmation of recurrent GBM or other glioma, circumscribed astrocytic glioma, or glioneuronalor neuronal tumors that has recurred. * Radiographically measurable disease. . -Karnofsky performance status ≥ 60. * Life expectancy ≥ 12 weeks. * Documentation of an actionable FGFR1-3 gene mutation or fusion/rearrangement from tissue : FGFR1-3 fusions or other rearrangements (FGFR1-3 in-frame fusions, any FGFR2 rearrangement, or FGFR1/3 rearrangement with known partner) or a defined FGFR1-3 activating mutation or in-frame deletion. Only participants with FGFR fusions or rearrangements with an intact kinase domain are eligible. * MRI-documented objective progression after prior therapy and must have no therapy available that is likely to provide clinical benefit. * Most recent archival tumor specimen must be a tumor block or a minimum of 15 unstained slides from biopsy or resection of primary tumor or metastasis. * Willingness to avoid pregnancy or fathering children. Exclusion Criteria: * Prior receipt of an FGFR inhibitor. * Receipt of anticancer medications or investigational drugs for any indication or reason within 28 days before first dose of study drug. * Participants may have had treatment for an unlimited number of prior relapses but must not have had prior bevacizumab or other VEGF/VEGFR inhibitors (exception: prior bevacizumab is allowed if it was administered for the treatment of radiation necrosis rather than progressive tumor and was stopped at least 12 weeks prior to MRI showing tumor progression). * Concurrent anticancer therapy * Candidate for potentially curative surgery. * Dexamethasone (or equivalent) \> 4 mg daily at the time of study registration * Current evidence of clinically significant corneal or retinal disorder as confirmed by ophthalmologic examination. * Diffuse leptomeningeal disease. * Radiation therapy administered within 12 weeks before enrollment/first dose of study drug. * Known additional malignancy that is progressing or requires active systemic treatment.

Locations (79)

Valkyrie Clinical Trials

Beverly Hills, California, United States

City of Hope National Medical Center

Duarte, California, United States

Providence Medical Foundation

Fullerton, California, United States

Usc Norris Comprehensive Cancer Center

Los Angeles, California, United States

Stanford Neuroscience Health Center

Sacramento, California, United States

Outcomes

Primary Outcomes

Objective Response Rate (ORR) in Participants With Recurrent Glioblastoma Based on Independent Central Review

ORR was defined as the percentage of participants who achieved a best overall response of complete response (CR) or partial response (PR) based on Response Assessment in Neuro-Oncology (RANO) as determined by an independent centralized radiological review committee. CR requires all of the following: disappearance of all enhancing measurable/nonmeasurable disease sustained for ≥4 weeks; no new lesions; stable/improved nonenhancing lesions; off corticosteroids/on physiologic replacement doses only and stable/improved clinically. PR requires all of the following: ≥50% decrease, compared with baseline, in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for ≥4 weeks; no progression of nonmeasurable disease; no new lesions; stable or improved nonenhancing lesions on same/lower dose of corticosteroids compared with baseline scan; on a corticosteroid dose not greater than the dose at time of baseline scan and stable/improved clinically.

Time frame: up to 651 days

Secondary Outcomes

ORR in Participants With Recurrent Non-glioblastoma Central Nervous System Tumors Based on Independent Central Review

ORR was defined as the percentage of participants who achieved a best overall response of CR or PR based on RANO as determined by an independent centralized radiological review committee. CR requires all of the following: disappearance of all enhancing measurable/nonmeasurable disease sustained for ≥4 weeks; no new lesions; stable/improved nonenhancing lesions; off corticosteroids/on physiologic replacement doses only and stable/improved clinically. PR requires all of the following: ≥50% decrease, compared with baseline, in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for ≥4 weeks; no progression of nonmeasurable disease; no new lesions; stable or improved nonenhancing lesions on same/lower dose of corticosteroids compared with baseline scan; on a corticosteroid dose not greater than the dose at time of baseline scan and stable/improved clinically.

Time frame: up to 784 days

Duration of Confirmed Response Based on Independent Central Review

Duration of response was defined as the time from the first assessment of confirmed CR or PR until progressive disease (PD) (according to RANO and assessed by an independent centralized radiological review committee) or death (whichever occurred first). Progression was defined by any of the following: ≥25% increase in the sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not due to comorbid events; the appearance of any new lesions; clear progression of nonmeasurable lesions; or definite clinical deterioration not attributable to other causes apart from the tumor, or to decrease in corticosteroid dose.

Time frame: up to 784 days

Duration of Unconfirmed Response Based on Independent Central Review

Duration of response was defined as the time from the first assessment of unconfirmed CR or PR until progressive disease (PD) (according to RANO and assessed by an independent centralized radiological review committee) or death (whichever occurred first). Progression was defined by any of the following: ≥25% increase in the sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not due to comorbid events; the appearance of any new lesions; clear progression of nonmeasurable lesions; or definite clinical deterioration not attributable to other causes apart from the tumor, or to decrease in corticosteroid dose.

Time frame: up to 784 days

ORR as Determined by Investigator Assessment

ORR was defined as the percentage of participants who achieved an unconfirmed best overall response of CR or PR based on RANO as determined by investigator assessment. CR requires all of the following: disappearance of all enhancing measurable/nonmeasurable disease sustained for ≥4 weeks; no new lesions; stable/improved nonenhancing lesions; off corticosteroids/on physiologic replacement doses only and stable/improved clinically. PR requires all of the following: ≥50% decrease, compared with baseline, in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for ≥4 weeks; no progression of nonmeasurable disease; no new lesions; stable or improved nonenhancing lesions on same/lower dose of corticosteroids compared with baseline scan; on a corticosteroid dose not greater than the dose at time of baseline scan and stable/improved clinically.

Time frame: up to 784 days

Number of Participants With Any Treatment-emergent Adverse Event (TEAE)

An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it was considered drug related. An AE could therefore have been any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug. A TEAE was defined as an AE reported for the first time or the worsening of a pre-existing event after the first dose of pemigatinib and within 30 days of the last dose of pemigatinib.

Time frame: up to 814 days

Number of Participants With Any ≥Grade 3 TEAE

An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it was considered drug related. A TEAE was defined as an AE reported for the first time or the worsening of a pre-existing event after the first dose of pemigatinib and within 30 days of the last dose of pemigatinib. The severity of AEs was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grades 1 through 5. Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment not indicated. Grade 2: moderate; minimal, local, or noninvasive treatment indicated; limiting age-appropriate activities of daily living. Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4: life-threatening consequences; urgent treatment indicated. Grade 5: fatal.

Time frame: up to 814 days

Number of Participants With TEAEs Leading to Discontinuation of Pemigatinib, Pemigatinib Dose Interruption, and Pemigatinib Dose Reduction

An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it was considered drug related. An AE could therefore have been any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug. A TEAE was defined as an AE reported for the first time or the worsening of a pre-existing event after the first dose of pemigatinib and within 30 days of the last dose of pemigatinib.

Time frame: up to 814 days

Disease Control Rate (DCR) Based on Independent Central Review

DCR was defined as the percentage of participants who achieved a best overall response of CR, PR, or stable disease (SD) based on RANO as determined by an independent centralized radiological review committee. In the case of SD, measurements must have met the SD criteria after the date of the first dose at a minimum interval of 42 days. SD occurred if the participant didn't qualify for CR, PR, or PD and required the following: stable nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan and clinically stable status.

Time frame: up to 784 days

Progression-free Survival (PFS) Based on Independent Central Review

PFS was defined as the time from the first dose until progressive disease (according to RANO and assessed by an independent centralized radiological review committee) or death (whichever occurred first). Progression was defined by any of the following: ≥25% increase in the sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not due to comorbid events; the appearance of any new lesions; clear progression of nonmeasurable lesions; or definite clinical deterioration not attributable to other causes apart from the tumor, or to decrease in corticosteroid dose.

Time frame: up to 784 days

Overall Survival

Overall survival was defined as the time from the first dose of study drug to death due to any cause.

Time frame: up to 784 days